Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. A virally encoded integrase protein mediates specific incorporation and integration of viral DNA into the host genome. Integration is essential for viral replication. Accordingly, inhibition of HIV integrase is an important therapeutic pursuit for treatment of HIV infection and related diseases.
Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, etal N. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). There is a need for new agents directed against alternate sites in the viral life cycle. Integrase has emerged as an attractive target, because it is necessary for stable infection and homologous enzymes are lacking in the human host (LaFemina, etal J. Virol. (1992) 66:7414-7419). The function of integrase is to catalyze integration of proviral DNA, resulting from the reverse transcription of viral RNA, into the host genome, by a stepwise fashion of endonucleolytic processing of proviral DNA within a cytoplasmic preintegration complex (termed 3′-processing or “3′-P”) with specific DNA sequences at the end of the HIV-1 long terminal repeat (LTR) regions, followed by translocation of the complex into the nuclear compartment where integration of 3′-processed proviral DNA into host DNA occurs in a “strand transfer” (ST) reaction (Hazuda, etal Science (2000) 287:646-650; Katzman, etal Adv. Virus Res. (1999) 52:371-395; Asante-Applah, etal Adv. Virus Res. (1999) 52:351-369). Although numerous agents potently inhibit 3′-P and ST in extracellular assays that employ recombinant integrase and viral long-terminal-repeat oligonucleotide sequences, often such inhibitors lack inhibitory potency when assayed using fully assembled preintegration complexes or fail to show antiviral effects against HIV-infected cells (Pommier, etal Adv. Virus Res. (1999) 52:427-458; Farnet, etal Proc. Natl. Acad. Sci. U.S.A. (1996) 93:9742-9747; Pommier, etal Antiviral Res. (2000) 47:139-148.
Certain HIV integrase inhibitors have been disclosed which block integration in extracellular assays and exhibit good antiviral effects against HIV-infected cells (Anthony, etal WO 02/30426; Anthony, etal WO 02/30930; Anthony, etal WO 02/30931; WO 02/055079; Zhuang, etal WO 02/36734; U.S. Pat. Nos. 6,395,743; 6,245,806; 6,271,402; Fujishita, etal WO 00/039,086; Uenaka etal WO 00/075,122; Selnick, etal WO 99/62513; Young, etal WO 99/62520; Payne, etal WO 01/00578; Jing, etal Biochemistry (2002) 41:5397-5403; Pais, etal Jour. Med. Chem. (2002) 45:3184-94; Goldgur, etal Proc. Natl. Acad. Sci. U.S.A. (1999) 96:13040-13043; Espeseth, etal Proc. Natl. Acad. Sci. U.S.A. (2000) 97:11244-11249).
HIV integrase inhibitory compounds with improved antiviral and pharmacokinetic properties are desirable, including enhanced activity against development of HIV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo (Nair, V. “HIV integrase as a target for antiviral chemotherapy” Reviews in Medical Virology (2002) 12(3):179-193; Young (2001) Current Opinion in Drug Discovery & Development, Vol. 4, No. 4, 402-410; Neamati (2002) Expert. Opin. Ther. Patents Vol. 12, No. 5, 709-724). Three-dimensional quantitative structure-activity relationship studies and docking simulations (Buolamwini, etal Jour. Med. Chem. (2002) 45:841-852) of conformationally-restrained cinnamoyl-type integrase inhibitors (Artico, etal Jour. Med. Chem. (1998) 41:3948-3960) have shown a large contribution of hydrogen-bonding interactions to the inhibitory activity differences among the compounds. Conformationally-constrained hydrogen-bonding functionality such as hydroxyl was correlated with inhibitory activity. Compounds with binding functionality in a pre-organized configuration may possess optimized inhibitory properties against HIV integrase. The prior art does not show or suggest compounds with integrase binding functionality in a pre-organized conformation or molecular structure. In addition to therapeutic uses, the value of compounds in diagnostic assays for HIV, for use in the preparation of polymers and for use as surfactants, and in other industrial utilities will be readily apparent to those skilled in the art.
Improving the delivery of drugs and other agents to target cells and tissues has been the focus of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g. to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or anti-viral drugs) that can be administered. By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g. blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells. Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells.